TRK inhibition in soft tissue sarcomas: A comprehensive review

Assi, Tarek; Rassy, Elie El; Nassereddine, Hussein; Farhat, Fadi; Karak, Fadi El; Kattan, Joseph; Ghosn, Marwan

doi:10.1053/j.seminoncol.2020.02.009

Cited by 11 publications

(5 citation statements)

References 59 publications

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“…The NTRK family of genes can be subjected to genomic alterations other than translocations, such as in‐frame deletions and point mutations, but, to date, only chromosomal translocations have been proven to be predictive of response to TRK inhibitors 9,33 . However, it is unknown whether accompanying genomic alterations and a more complex karyotype may impact on the efficacy of TRK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Chromosomal imbalances detected in NTRK‐rearranged sarcomas by the use of comparative genomic hybridisation

et al. 2021

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Aims NTRK‐rearranged sarcomas are emerging as a distinct class of sarcomas of particular importance in the era of targeted therapy. The aim of this study was to use array comparative genomic hybridisation (aCGH) to explore the cytogenetic profile of six adult soft tissue sarcomas harbouring NTRK gene fusions. Methods and results aCGH was performed on six adult soft tissue sarcomas with proven NTRK rearrangements [NTRK1, n = 1 (TPM3–NTRK1); NTRK2, n = 1 (MTMR2–NTRK2); NTRK3, n = 4 (two ETV6–NTRK3; two with unknown partners). The morphological patterns of these cases included inflammatory myofibroblastic tumour‐like, fibrosarcoma/malignant peripheral nerve sheath tumour‐like, and Ewing sarcoma‐like. On the basis of the number of chromosomal copy number variations (CNVs), ranging from two to 15 per sample, NTRK‐associated sarcomas could be subdivided into two groups: one with a relatively simple karyotype (n = 2; median of three genomic alterations), and those with a more complex karyotype (n = 4; median of 11 genomic imbalances). Recurrent chromosomal CNVs included gains at chromosomes 6p, 1q, 7 (whole chromosome), and 12p, and losses at chromosomes 10q, 13q, 19q, and 9p. Conclusions NTRK‐rearranged sarcomas constitute a heterogeneous group of tumours that can show a relatively simple or a complex karyotype. Although there were some, but inconsistent, associations between karyotype complexity and morphology, our study showed that a more complex karyotype in this group of tumours appeared to correlate with more aggressive clinical behaviour. Gains at chromosome 6p and 1q were the most common recurrent genomic alterations, being present in 67% of the samples (4/6), followed by gains at chromosome 7, which were present in 50% of the samples (3/6).

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Section: Discussionmentioning

confidence: 99%

“…larotrectinib) or multikinase inhibitors (e.g. entrectinib, crizotinib, altiratinib, ponatinib, foretinib, nintedanib, and sitravatinib, among others) (reviewed in Assi et al 9 …”

Section: Introductionmentioning

confidence: 99%

Chromosomal imbalances detected in NTRK‐rearranged sarcomas by the use of comparative genomic hybridisation

et al. 2021

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“…So, it is the rst time reported another NTRK3 fusion type, and it is a little different in the clinical response of Larotrectinib, which in our patient only got a stable disease (SD) result. Unresponsiveness to an NTRK inhibitor may be due either to the lack of an NTRK fusion or to the development of a resistance mechanism [24], such as acquired mutations in the kinase domain of the NTRK genes [25], including a mutation in NTRK3 that changes amino acid 623 in TRKC from glycine to arginine (G623R) or a similar mutation in the paralogous residue, G595R of NTRK1/TRKA. In the 2020 ASCO case report [26], they had discussed response and mechanisms of resistance to Larotrectinib and Selitrectinib in metastatic undifferentiated sarcoma harboring an oncogenic fusion of NTRK1, and they discovered the NTRK1 solvent-front mutation, which facilitates the tumor initially developed resistance to Larotrectinib.…”

Section: Discussionmentioning

confidence: 99%

The First Case Treated with Larotrectinib of a Novel TMTC2-NTRK3 Fusion Undifferentiated High-Grade Pleomorphic Sarcoma of the Chest

Bai

Zhang

Wang

et al. 2021

Preprint

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Undifferentiated high-grade pleomorphic sarcoma (UPS) is a rare soft tissue sarcoma (STS) of mesenchymal origin, particularly the extremities and retroperitoneum, meanwhile it has been reported in almost all parts of the body. UPS is highly invasive and has a poor prognosis due to its clinical manifestations of painless mass and deep tumor site, which are usually found at an advanced stage. Patients with UPS tend to have a lower 5-year survival rate than patients with other types of STS. Recently, NTRK fusions were detected in many cancer types, such as thyroid cancer, colorectal cancer, non-small cell lung cancer, soft tissue tumors, uterine sarcomas, and melanomas. However, the mutation frequency of NTRK fusion in all cancers is only 0.1-1%. Targeted therapy with NTRK inhibitors, such as Larotrectinib and Entrectinib, leads to a response in most patients with NTRK1/2/3 gene fusion-positive tumors. Herein, we present a 68-years old man diagnosed with stage IIIA (T2N0M0G3) UPS. Next-generation sequencing (NGS) revealed a novel TMTC2-NTRK3 fusion. The NTRK3 positivity was also detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). He had a response to Larotrectinib. This report broadens the spectrum of NTRK fusions in UPS and highlights a new target for treatment.

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“…Additionally, approximately 80 NTRK fusion partners have also been described ( 10 , 11 ). Although the frequency of NTRK fusions is low, they are ubiquitous in rare cancer types, such as mammary analog secretory carcinoma and infantile fibrosarcoma ( 12 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic Features of Solid Tumor Patients Harboring ALK/ROS1/NTRK Gene Fusions

Dai

Liu²,

He³

et al. 2022

Front. Oncol.

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The fusions of receptor tyrosine kinase (RTK) involving anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and neurotrophic receptor tyrosine kinase (NTRK) represent the potential targets of therapeutic intervention for various types of solid tumors. Here, the genomic features of 180 Chinese solid tumor patients with ALK, ROS1, and NTRK fusions by next generation sequencing (NGS) were comprehensively characterized, and the data from 121 patients in Memorial Sloan Kettering Cancer Center (MSKCC) database were used to compare. We found that ALK, ROS1, and NTRK fusions were more common in younger female patients (p<0.001) and showed a higher expression of programmed death ligand 1 (PD-L1). The gene-intergenic fusion and the fusion with rare formation directions accounted for a certain proportion in all samples and 62 novel fusions were discovered. Alterations in TP53 and MUC16 were common in patients with RTK fusions. The mutational signatures of patients were mainly distributed in COSMIC signature 1, 2, 3, 15 and 30, while had a higher frequency in copy number variations (CNVs) of individual genes, such as IL-7R. In the MSKCC cohort, patients with fusions and CNVs showed shorter overall survival than those with only fusions. Furthermore, the differentially mutated genes between fusion-positive and -negative patients mainly concentrated on MAPK signaling and FOXO signaling pathways. These results may provide genomic information for the personalized clinical management of solid tumor patients with ALK, ROS1, and NTRK fusions in the era of precision medicine.

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TRK inhibition in soft tissue sarcomas: A comprehensive review

Cited by 11 publications

References 59 publications

Chromosomal imbalances detected in NTRK‐rearranged sarcomas by the use of comparative genomic hybridisation

Chromosomal imbalances detected in NTRK‐rearranged sarcomas by the use of comparative genomic hybridisation

The First Case Treated with Larotrectinib of a Novel TMTC2-NTRK3 Fusion Undifferentiated High-Grade Pleomorphic Sarcoma of the Chest

Genomic Features of Solid Tumor Patients Harboring ALK/ROS1/NTRK Gene Fusions

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